Therapeutically, an antagonist which possesses both kinase selectivity for protein kinase C (PKC) and PKC isozyme selectivity is a potentially useful pharmacological agent. Hartenstein, J. H., et al., in "perspectives in Medicinal Chemistry," 99-118 (1993), VCH Publishers, New York. Such an antagonist of protein kinase C would be useful in treating disease states in which PKC has been implicated. Lester, D. S., et al., "Protein Kinase C: Current concepts and Future Perspectives", Ellis Horwood New York (1992). Specific isozymes of protein kinase C have been implicated in cancer (Ahmed, et al., Mol. Pharma., 43, 858-86 (1993), CNS diseases such as Alzheimer's; Demaerschalck, et al., Biochem. Biophys. Acta. 1181, 214-218 (1993), cardiovascular disease; (Natarajan et al. Mol. Cell. Endo., 101, 59-66 (1994)) and diabetic complications; King, et al., Proc. Nat. Acad. Sciences (USA), 88:22, 11059-63 (1992).
Recently, bisindolylmalimides of the formula: ##STR2## have been recognized as PKC selective agents and have shown promise as therapeutic agents for treating diseases implicated by PKC. Bit, et al., J. Med. Chem. 36:21 (1993). Wikinson S. E., et al., Biochem J., 299, 335 (1993). Toullec, D., et al., J. Biol. Chem., 266, 15771 (1991); Davis, P. D., et al., J. Med. Chem., 35, 177 (1992).
U.S. patent application Ser. No. 08/163,060 discloses a novel class of compounds that are potent and effective inhibitors of PKC. These compounds are of the Formula (I): ##STR3## and are prepared by coupling a bisindolylmaleimide with a linker of the Formula (II): ##STR4## form the N to N linked bisindolylmaleimide.
The present invention provides novel compounds of the Formula (II) and the stereoselective synthesis of these compounds. Under the preferred conditions, the compounds are produced in high yield and without utilizing expensive chromatographic separations. The synthesis is particularly advantageous because it further provides a stereoselective route of preparing the compounds of the Formula (I).